The aim of this proposal is to define the mechanisms responsible for vaccination against gamma-herpesvirus latency. Understanding these mechanisms will contribute to understanding the fundamentals of immunity to gamma-herpesviruses. Infection with two human gamma-herpesviruses, Epstein-Barr Virus (EBV) and Kaposi's sarcoma associated herpesvirus (KSHV, HHVS), is associated with tumors and lymphoproliferative disease especially in AIDS patients and transplant recipients. The mechanisms of immunity to gamma-herpesviruses are incompletely understood and there are no effective vaccines against these viruses. We have used infection of mice with gamma-HV68 (MHV-68), a virus closely related to EBV and KSHV which infects laboratory mice, to define mechanisms of gamma-herpesvirus pathogenesis and immunity. Surprisingly, subunit vaccination approaches used by several other groups effectively control acute gamma-HV68 infection but fail to prevent long term latency. This proposal is based on a novel observation made in our lab that infection with a reactivation deficient v-cyclin gamma-HV68 mutant virus effectively vaccinates against establishment of latency by wildtype. gamma-HV68. Further studies using a newly developed transgenic mouse model have shown that, while B cells are required for vaccination, antibody is not required. This new model provides us an opportunity to directly evaluate the contributions of immune T cells to vaccination against latency without confounding effects of immune antibody. This proposal will define, through the following Aims, the mechanisms responsible for vaccination against latency, thereby extending our fundamental understanding of how the immune system controls chronic viral infection and disease. The two underlying hypotheses being tested are that latency antigen specific T cells are: (i) required for prevention of the establishment of latency, and (ii) can eliminate latently infected cells. Aim 1) Determine the role of CD4 and CD8 T cells in vaccination against. HV68 latencyAim 2) Identify latency associated antigens recognized by T cells Aim 3) Test the effects of vaccination with latency associated antigens.